1492Ch22

Manahan,StanleyE.TOXICOLOGICALCHEMISTRYEnvironmentalChemistryBocaRaton:CRCPressLLC,200022TOXICOLOGICALCHEMISTRY____________________________________________________22.1.INTRODUCTIONTOTOXICOLOGYANDTOXICOLOGICALCHEMISTRYUltimately,mostpollutantsandhazardoussubstancesareofconcernbecauseoftheirtoxiceffects.Thegeneralaspectsoftheseeffectsareaddressedinthischapterundertheheadingoftoxicologicalchemistry;thetoxicologicalchemistryofspecificclassesofchemicalsubstancesisaddressedinChapter23.Inordertounderstandtoxicologicalchemistry,itisessentialtohavesomeunderstandingofbiochemistry,thesciencethatdealswithchemicalprocessesandmaterialsinlivingsystems.BiochemistrywassummarizedinChapter21.ToxicologyApoison,ortoxicant,isasubstancethatisharmfultolivingorganismsbecauseofitsdetrimentaleffectsontissues,organs,orbiologicalprocesses.Toxicologyisthescienceofpoisons.Thesedefinitionsaresubjecttoanumberofqualifications.Whetherasubstanceispoisonousdependsuponthetypeoforganismexposed,theamountofthesubstance,andtherouteofexposure.Inthecaseofhumanexposure,thedegreeofharmdonebyapoisoncandependstronglyuponwhethertheexposureistotheskin,byinhalation,orthroughingestion.Toxicantstowhichsubjectsareexposedintheenvironmentoroccupationallymaybeinseveraldifferentphysicalforms.Thismaybeillustratedfortoxicantsthatareinhaled.Gasesaresubstancessuchascarbonmonoxideinairthatarenormallyinthegaseousstateunderambientconditionsoftemperatureandpressure.Vaporsaregas-phasematerialsthathaveevaporatedorsublimedfromliquidsorsolids.Dustsarerespirablesolidparticlesproducedbygrindingbulksolids,whereasfumesaresolidparticlesfromthecondensationofvapors,oftenmetalsormetaloxides.Mistsareliquiddroplets.Oftenatoxicsubstanceisinsolutionormixedwithothersubstances.Asub-stancewithwhichthetoxicantisassociated(thesolventinwhichitisdissolvedor©2000CRCPressLLCthesolidmediuminwhichitisdispersed)iscalledthematrix.Thematrixmayhaveastrongeffectuponthetoxicityofthetoxicant.Therearenumerousvariablesrelatedtothewaysinwhichorganismsareexposedtotoxicsubstances.Oneofthemostcrucialofthese,dose,isdiscussedinSection22.2.Anotherimportantfactoristhetoxicantconcentration,whichmayrangefromthepuresubstance(100%)downtoaverydilutesolutionofahighlypotentpoison.Boththedurationofexposureperexposureincidentandthefrequencyofexposureareimportant.Therateofexposureandthetotaltimeperiodoverwhichtheorganismisexposedarebothimportantsituationalvariables.Theexposuresiteandroutealsoaffecttoxicity.Itispossibletoclassifyexposuresonthebasisofacutevs.chronicandlocalvs.systemicexposure,givingfourgeneralcategories.Acutelocalexposureoccursataspecificlocationoveratimeperiodofafewsecondstoafewhoursandmayaffecttheexposuresite,particularlytheskin,eyes,ormucousmembranes.Thesamepartsofthebodycanbeaffectedbychroniclocalexposure,forwhichthetimespanmaybeaslongasseveralyears.Acutesystemicexposureisabriefexposureorexposuretoasingledoseandoccurswithtoxicantsthatcanenterthebody,suchasbyinhalationoringestion,andaffectorgans,suchastheliver,thatareremotefromtheentrysite.Chronicsystemicexposurediffersinthattheexposureoccursoveraprolongedtimeperiod.Indiscussingexposuresitesfortoxicantsitisusefultoconsiderthemajorroutesandsitesofexposure,distribution,andeliminationoftoxicantsinthebodyasshowninFigure22.1.Themajorroutesofaccidentalorintentionalexposuretotoxicantsbyhumansandotheranimalsaretheskin(percutaneousroute),thelungs(inhalation,respiration,pulmonaryroute),andthemouth(oralroute);minorroutesofexposurearerectal,vaginal,andparenteral(intravenousorintramuscular,acommonmeansfortheadministrationofdrugsortoxicsubstancesintestsubjects).Thewaythatatoxicsubstanceisintroducedintothecomplexsystemofanorganismisstronglydependentuponthephysicalandchemicalpropertiesofthesubstance.Thepulmonarysystemismostlikelytotakeintoxicgasesorveryfine,respirablesolidorliquidparticles.Inotherthanarespirableform,asolidusuallyentersthebodyorally.Absorptionthroughtheskinismostlikelyforliquids,solutesinsolution,andsemisolids,suchassludges.Thedefensivebarriersthatatoxicantmayencountervarywiththerouteofexposure.Forexample,toxicelementalmercuryisabsorbedthroughthealveoliinthelungsmuchmorereadilythanthroughtheskinorgastrointestinaltract.Mosttestexposurestoanimalsarethroughingestionorgavage(introductionintothestomachthroughatube).Pulmonaryexposureisoftenfavoredwithsubjectsthatmayexhibitrefractorybehaviorwhennoxiouschemicalsareadministeredbymeansrequiringadegreeofcooperationfromthesubject.Intravenousinjectionmaybechosenfordeliberateexposurewhenitisnecessarytoknowtheconcentrationandeffectofaxenobioticsubstanceintheblood.However,pathwaysusedexperimentallythatarealmostcertainnottobesignificantinaccidentalexposurescangivemisleadingresultswhentheyavoidthebody’snaturaldefensemechanisms.Aninterestinghistoricalexampleoftheimportanceoftherouteofexposuretotoxicantsisprovidedbycancercausedbycontactofcoaltarwithskin.Themajorbarriertodermalabsorptionoftoxicantsisthestratumcorneum,orhornylayer.©2000CRCPressLLCDistributionoffree,bound,ormetaboliteformLiverBileFeces(excretion)Bloodandlymphsyst